Constitutional Symptoms Masking COVID-19 In A Patient with Primary Myelofibrosis

1. Abstract

Constitutional symptoms of primary myelofibrosis can mask COVID-19 infection. We present the case of a patient with primary myelofibrosis on ruxolitinib who tested positive for COVID-19 as part of Hematopoietic Stem Cell Transplant (HSCT) workup. The patient was asymptomatic and took over four weeks to develop a negative COVID-19 RT-PCR test. She did not test positive for COVID-19 antibodies. Patients with hematologic malignancies such as primary myelofibrosis or patients taking immunosuppressive therapy, such as ruxolitinib, may not develop infectious symptoms from COVID-19. In addition, they may take longer to test negative and may not develop antibodies to COVID-19. Therefore, these patients may be more vulnerable to re-infection. Although ruxolitinib may contribute to immunosuppression and increased susceptibility to infection, the drug is being studied as a possible treatment for COVID-19. To improve safety and patient outcomes, it is critical to test patients for COVID-19 prior to HSCT as clinicians cannot rely on symptoms to determine infection.

2. Keywords

Primary myelofibrosis; Hematopoietic stem cell transplant; COVID-19; Ruxolitinib

3. Introduction

Primary Myelofibrosis (MF) is a clonal myeloproliferative neoplasm which presents with anemia, splenomegaly, and constitutional symptoms, including severe fatigue and fever [1]. The exact molecular mechanism of MF pathogenesis is not known [2]. In the bone marrow, clonal proliferation of hematopoietic stem cells is thought to result in cytokine release, myeloid hyperproliferation, and bone marrow fibrosis [3]. Driver mutations of genes including JAK2, CALR, and MPL have been identified [3]. The only curative treatment is hematopoietic stem cell transplant (HSCT) [1]. The mutation-enhanced international prognostic score system for transplantation-age patients (MIPSS70) provides risk stratification to identify appropriate candidates for HSCT, which carries its own significant morbidity [4]. Once a patient is identified for transplant, an extensive examination, including infectious workup, should be pursued. In the new age of Coronavirus disease 2019 (COVID-19), it is more important than ever to determine if a patient has an infection prior to cancer directed therapy, especially prior to HSCT. COVID-19 is a novel viral respiratory infection that has rapidly caused a global pandemic. The infection has variable presentations in different hosts. Up to 40-45% of COVID-19 cases may be asymptomatic [5]. However, classic symptoms include fever, cough, and dyspnea, anosmia, and diarrhea [6]. COVID-19 infection can be diagnosed by reverse transcription polymerase chain reaction (RT-PCR) as well as point-of-care (POC) antigen detection. There are various possible RT-PCR targets in the viral genome, which contains approximately 30,000 nucleotides and 15 genes [7]. These include the envelope, nucleocapsid, RNA-dependent RNA polymerase, non-structural protein 10, and non-structural protein 14, exoribonuclease [7]. Mutations and variations in the sequence can limit this method [7]. Point-of care testing is less sensitive than the RT-PCR, and a negative RT-PCR result does not exclude COVID-19 infection [7]. In addition to initial testing for COVID-19, antibody assays have been developed to detect the immune response to infection. One study of 285 subjects showed 100% of patients tested positive for antiviral immunoglobin G (IgG) within 19 days of symptom onset [8]. In addition, 7 of 148 close contacts of COVID-19 patients with initial negative RT-PCR tests were found to have positive IgG and/or immunoglobin M (IgM) antibodies [8]. Another study in Wuhan, China found 55 of 66 confirmed COVID-19 cases to test positive for IgG antibodies [9]. We present the case of a patient with primary MF who was incidentally diagnosed with COVID-19 prior to stem cell transplant and her lack of ability to mount an immune response.

4. Case Report

The patient is a 67-year-old woman with high-risk primary MF on ruxolitinib and End-stage Renal Disease (ESRD) who tested positive for COVID-19 the week prior to planned HSCT. The patient was considered high-risk based on MIPSS70 score, mainly driven by anemia, thrombocytopenia, and constitutional symptoms. She had longstanding low-grade fevers for five years that were attributed to MF. As part of standard workup prior to transplant, she tested positive for COVID-19 by RT-PCR in the absence of any symptoms. She specifically denied cough, shortness of breath, sore throat, abdominal pain, and diarrhea prior to diagnosis. She reported social distancing but was in contact with her husband and daughter. Both family members had been asymptomatic. At time of diagnosis, the patient had a single fever to 39°C which quickly defervesced. She was hemodynamically stable with baseline tachycardia and was not hypoxic on room air. Labs were notable for lymphopenia, thrombocytopenia, and mild coagulopathy (absolute lymphocyte count 0.4 thous/ul, platelets 61 thous/ul, prothrombin time 15.6 sec, partial thromboplastin time 42 sec, international normalized ratio 1.2). Chest radiograph was unremarkable. Other inflammatory markers were not obtained. See (Table1).

5. Discussion

This case describes a patient with primary MF who was incidentally diagnosed with COVID-19. In the setting of chronic constitutional manifestations of MF and the fact that she had been having fevers for months prior to the COVID-19 pandemic, there was no distinct clinical sign of infection. Had she not been tested for COVID-19 prior to transplant, her infection may not have been diagnosed and she may have had a worse outcome. It is now standard of care to test all patients prior to transplant, because it cannot be assumed that an asymptomatic patient is not infected with COVID-19. In addition, resolution of COVID-19 in this patient was determined based on RT-PCR given that her fevers would continue at baseline due to MF. The patient had negative COVID-19 IgG antibody testing 31 days after initial diagnosis. This is unusual given that Huang et al. observed 100% IgG seroconversion within 19 days [8]. In addition, Ma et al. detected IgG and IgM as early as four days after symptom onset, with IgG sharply increasing on the 12th day. Sensitivity of IgG was reported to be 83.3% [9]. The immunological derangements associated with primary MF, as well as concomitant immunosuppressive treatment with ruxolitinib may have prevented IgG formation.

6. Conclusion

Primary MF and immunosuppressive therapies may mask COVID-19 symptoms and prevent or delay seroconversion. Patients with MF, especially when undergoing HSCT, should be screened for COVID-19 and monitored carefully to improve safety. Clinicians cannot rely on symptoms as indicators of COVID-19 infection, particularly in patients with MF.

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Schwartz C. Constitutional Symptoms Masking COVID-19 In A Patient with Primary Myelofibrosis. Annals of Clinical and Medical Case Reports 2020